Complicaciones del trasplante de células madre hematopoyéticas en pediatría, enfermedad de injerto contra huésped y efectos tardíos (PDQ®)–Versión para profesionales de salud

Debido a la intensidad de la terapia relacionada con el proceso de trasplante, el estado clínico del receptor antes del procedimiento (que abarca aspectos como la edad, la presencia de infecciones o disfunción orgánica, y el estado funcional) se vincula con el riesgo de mortalidad relacionada con el trasplante.

La mejor herramienta para evaluar la repercusión de comorbilidades anteriores al trasplante sobre los desenlaces posteriores se formuló mediante la adaptación de una escala de comorbilidad ya existente, el Charlson Comorbidity Index (CCI). Investigadores del Fred Hutchinson Cancer Research Center definieron en forma sistemática qué elementos del CCI se correlacionaban con la mortalidad relacionada con el trasplante en adultos y niños. También determinaron varias afecciones comórbidas que tienen una capacidad de predicción específica para pacientes que reciben trasplantes.

Gracias a una validación exitosa se logró definir un índice de comorbilidad específico para el trasplante de células hematopoyéticas que ahora se denomina Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI).[1,2] La tasa de mortalidad relacionada con el trasplante aumenta cuando hay comorbilidades cardíacas, hepáticas, pulmonares, gastrointestinales, infecciosas y autoinmunitarias, o antecedentes de tumores sólidos (consultar el Cuadro 1).

Este índice tiene gran poder predictivo para la mortalidad relacionada con el trasplante y la supervivencia general (SG); el cociente de riesgos instantáneos es de 3,54 (intervalo de confianza [IC] 95 %, 2,0–6,3) para la mortalidad sin recaída y de 2,69 (IC 95 %, 1,8–4,1) para la supervivencia de pacientes con puntaje de 3 o superior en comparación con aquellos con puntaje de 0. Aunque en los estudios originales participaron pacientes tratados con abordajes mielosupresores intensivos, se observó que el HCT-CI también predice los desenlaces de los pacientes tratados con regímenes no mielosupresores de intensidad reducida.[3] El índice también se combinó con el estado de la enfermedad [4] y el puntaje de Karnofsky,[5] lo que condujo a un pronóstico incluso mejor de los resultados de supervivencia. Asimismo, los puntajes altos de HCT-CI (>3) se han relacionado con un riesgo más elevado de enfermedad de injerto contra huésped (enfermedad de injerto contra receptor) aguda de grados III a IV.[6]

La mayoría de pacientes evaluados en los estudios de HCT-CI han sido adultos y las comorbilidades enumeradas están sesgadas por las enfermedades de los adultos. La importancia de esta escala para los receptores pediátricos y adultos jóvenes de trasplante de células madre hematopoyéticas (TCMH) se evaluó en varios estudios.

Evidencia (uso del puntaje HCT-CI en pediatría):

La mayoría de las afecciones comórbidas notificadas fueron afecciones respiratorias o hepáticas, e infecciones.[7,8] En el estudio de adolescentes y adultos jóvenes, los pacientes con disfunción pulmonar previa al TCMH tuvieron un riesgo especialmente alto de comorbilidad, con una tasa SG a 2 años del 29 % en comparación con el 61 % en los pacientes con funcionamiento pulmonar normal antes del TCMH.[8]

Bibliografía

1. Sorror ML, Maris MB, Storb R, et al.: Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106 (8): 2912-9, 2005. [PUBMED Abstract]
2. ElSawy M, Storer BE, Pulsipher MA, et al.: Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation. Br J Haematol 170 (4): 574-83, 2015. [PUBMED Abstract]
3. Sorror ML, Storer BE, Maloney DG, et al.: Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood 111 (1): 446-52, 2008. [PUBMED Abstract]
4. Sorror ML, Sandmaier BM, Storer BE, et al.: Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25 (27): 4246-54, 2007. [PUBMED Abstract]
5. Sorror M, Storer B, Sandmaier BM, et al.: Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 112 (9): 1992-2001, 2008. [PUBMED Abstract]
6. Sorror ML, Martin PJ, Storb RF, et al.: Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood 124 (2): 287-95, 2014. [PUBMED Abstract]
7. Smith AR, Majhail NS, MacMillan ML, et al.: Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients. Blood 117 (9): 2728-34, 2011. [PUBMED Abstract]
8. Wood W, Deal A, Whitley J, et al.: Usefulness of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in predicting outcomes for adolescents and young adults with hematologic malignancies undergoing allogeneic stem cell transplant. Pediatr Blood Cancer 57 (3): 499-505, 2011. [PUBMED Abstract]
9. Sorror ML, Logan BR, Zhu X, et al.: Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 21 (8): 1479-87, 2015. [PUBMED Abstract]

Riesgo de infecciones y recuperación inmunitaria después del trasplante

La reconstitución inmunitaria defectuosa es un obstáculo importante para un TCMH satisfactorio, con independencia de la fuente del injerto.[1,2] Se observó que las infecciones graves dan cuenta de un porcentaje significativo (4–20 %) de muertes tardías después de un TCMH.[3]

Los factores que puede demorar significativamente la recuperación inmunitaria son los siguientes:[4]

• Manipulación del injerto (eliminación de células T).
• Fuente de células madre (recuperación lenta con sangre de cordón umbilical).
• Enfermedad de injerto contra huésped (EICH) crónica.

En la Figura 1 se muestran los defectos inmunitarios, los factores relacionados con el trasplante que afectan la recuperación inmunitaria, y los tipos y la cronología de las infecciones que se presentan después de un trasplante alogénico.[5]

Ampliar

Las infecciones bacterianas tienden a presentarse en las primeras semanas después del trasplante durante la fase neutropénica, cuando las barreras mucosas se dañan con el régimen de acondicionamiento. Hay investigaciones importantes en curso sobre la función de los fármacos antibacterianos profilácticos durante la fase neutropénica.[6]

En un esfuerzo conjunto, los centros para el Control y la Prevención de Enfermedades, la Infectious Disease Society of America y la American Society of Transplantation and Cellular Therapy establecieron directrices para la prevención de infecciones después del TCMH.[7] Los abordajes incluyen antivirales, antifúngicos y antibióticos preventivos o profilácticos; el aumento gradual de la dosis para administrar terapia empírica intensa cuando aparecen signos de infección, y el seguimiento minucioso continuado durante todo el periodo de inmunodepresión después del trasplante.

La profilaxis contra infecciones fúngicas es estándar durante los primeros meses después del trasplante y en ocasiones se considera para los pacientes con EICH crónica que tienen un riesgo alto de presentar estas infecciones. La profilaxis antifúngica se debe adaptar al estado inmunitario subyacente del paciente. Las infecciones por Pneumocystis se pueden presentar en todos los pacientes después de un trasplante de médula ósea y la profilaxis es imprescindible.[6]; [8][Nivel de evidencia C1]

Las infecciones víricas son una causa importante de mortalidad después de un TCMH, en particular después de procedimientos de reducción de células T o con sangre de cordón umbilical. Algunos tipos de infecciones víricas son los siguientes:

• Infección por citomegalovirus (CMV). La infección por CMV fue una causa importante de mortalidad en el pasado, pero en la actualidad, se cuenta con fármacos eficaces para su tratamiento. Además, se han elaborado estrategias preventivas, como la vigilancia mediante reacción en cadena de la polimerasa (PCR) cuantitativa seguida de terapia presintomática con ganciclovir.
• Infección por el virus de Epstein-Barr (VEB). En raras ocasiones, este virus causa una enfermedad linfoproliferativa que por lo general se relaciona con la terapia multifarmacológica intensiva del EICH o un TCMH con reducción de células T.
• Infección por adenovirus. La infección por adenovirus es un problema importante en el entorno de un trasplante con reducción de células T; la vigilancia mediante PCR cuantitativa en sangre seguida de terapia con cidofovir o brincidofovir (disponible mediante un protocolo de uso compasivo) ha conducido a una disminución notable de la morbilidad.[9]
• Otros virus. Se han involucrado otros virus en la cistitis hemorrágica (virus BK), la encefalitis y la recuperación precaria del recuento sanguíneo (virus del herpes humano 6), así como en otros problemas clínicos.[6] En un estudio se indicó que las cargas virales elevadas de BK poco después del trasplante (4–7 semanas) quizás estén relacionadas con la reducción a largo plazo de la tasa de filtración glomerular.[10]

La vigilancia vírica minuciosa es esencial durante los procedimientos alogénicos de riesgo alto.

Se pueden presentar infecciones bacterianas tardías en pacientes con vías centrales o pacientes que tienen EICH crónica grave. Estos pacientes son susceptibles a infecciones por microorganismos encapsulados, en particular el neumococo. A pesar de la revacunación, estos pacientes a veces presentan infecciones graves; se recomienda la profilaxis continua hasta que se documente una respuesta serológica a la vacunación. En ocasiones, los pacientes presentan asplenia funcional después de un TCMH alogénico y se recomienda la profilaxis antibiótica. Los pacientes deben continuar recibiendo profilaxis antiinfecciosa (por ejemplo, contra la neumonía por Pneumocystis jirovecii) hasta la recuperación inmunitaria. El tiempo de recuperación inmunitaria no es uniforme, pero oscila de 3 a 9 meses después de un TCMH autógeno y de 9 a 24 meses después de TCMH alogénico sin EICH. Es posible que los pacientes con EICH crónica activa presenten inmunodepresión persistente durante años. Muchos centros hacen un seguimiento de la recuperación del subconjunto de células T después de los trasplantes de médula ósea para determinar el riesgo de infección.[6]

Vacunación después de un trasplante

Los grupos internacionales de trasplantes y enfermedades infecciosas han elaborado directrices específicas para la administración de vacunas después de trasplantes autógenos y alogénicos.[6,11,12] No se han realizado estudios comparativos destinados a definir el momento oportuno de la vacunación después del trasplante, pero las directrices de vacunación descritas en el Cuadro 2 conducen a valores de anticuerpos protectores en la mayoría de los pacientes vacunados. En estas directrices se recomienda que los receptores de trasplantes autógenos reciban vacunas 6 meses después de la infusión de células madre y vacunas elaboradas con microbios vivos 24 meses después del trasplante. Los pacientes sometidos a procedimientos alogénicos pueden comenzar las vacunaciones a los 6 meses del trasplante. Sin embargo, en el caso de pacientes que permanecen con inmunodepresión, muchos grupos prefieren esperar hasta 12 meses después del procedimiento o hasta que ya no reciban inmunodepresores.

Se deben analizar las directrices de vacunación cuando se producen brotes de enfermedades endémicas locales o epidémicas. En esos entornos, es posible establecer la vacunación con vacunas inactivadas, teniendo en cuenta que producen respuestas limitadas en el huésped.

Cuadro 2. Esquema de vacunación para receptores de trasplante de células madre hematopoyéticasa

TCMH autógeno	6 mesesb	8 mesesb	12 mesesb	24 mesesb
TCMH alogénico (si no se vacunó en los primeros 12 meses después del TCMH; empezar la vacunación con independencia del estado de la EICH o la inmunodepresión)	12 mesesb (antes, si ya no recibe inmunodepresores)	14 mesesb (o 2 meses después de la primera dosis)	18 mesesb (o 6 meses después de la primera dosis)	24 mesesb
EICH = enfermedad de injerto contra huésped; TCMH = trasplante de células madre hematopoyéticas.
aAdaptado de Tomblyn et al.,[6] Centros para el Control y la Prevención de Enfermedades,[7] y Kumar et al.[13]
bLos tiempos indicados son posteriores al trasplante (día 0).
cSe puede usar Tdap si no se dispone de DTap.
dEs posible considerar los valores de anticuerpos para pacientes pediátricos y pacientes de EICH que recibieron vacunas mientras se sometían a inmunodepresión (6–8 semanas como mínimo después de la última vacunación).
eEn ocasiones, se comienza 4 meses después del TCMH o antes para pacientes con recuentos de CD4 >200/μl o en cualquier momento durante una epidemia. Si se administra <6 meses después de un TCMH, es posible que se necesite una segunda dosis. Los niños menores de 9 años necesitan una segunda dosis 1 mes después de la primera.
fConsiderar los valores de anticuerpos antes y después de la vacunación (por lo menos 6–8 semanas después).
gPCV 7 a los 24 meses solo para pacientes con EICH; todos los otros pacientes pueden recibir PPV 23.
hLos pacientes pediátricos deben recibir 2 dosis con 1 mes de diferencia como mínimo.
Vacunas inactivadas
Vacuna acelular contra la difteria, el tétanos y la tosferina (DTap)	Xc	Xc	Xc,d
Vacuna contra Haemophilus influenzae (Hib)	X	X	Xd
Vacuna contra la hepatitis B (HepB)	X	X	Xd
Vacuna antipoliomielítica inactivada (IPV)	X	X	Xd
Vacuna antigripal estacional (intramuscular)	Xe
Vacunas antineumocócicas conjugadas (PCV 7, PCV 13)	Xf	X	Xd,f,g
Vacuna antineumocócica de polisacáridos (PPV 23)			Xd,f,g
Vacunas con microbios vivos atenuadas (contraindicadas en pacientes con EICH activa o sometidos a inmunodepresión)
Vacuna contra el sarampión, la parotiditis y la rubéola				Xd,h
Opcional: vacunas inactivadas
Vacuna contra la hepatitis A			Opcional
Vacuna antimeningocócica			Xd (para pacientes con riesgo alto)
Opcional: vacunas con microbios vivos (contraindicadas en pacientes con EICH activa o sometidos a inmunodepresión)
Vacuna contra la varicela				Opcional
Vacuna antirrábica			En caso de exposición, es posible que se considere a los 12–24 meses
Vacunas contra la fiebre amarilla, la encefalitis transmitida por garrapatas (TBE) y la encefalitis japonesa B				Para viajar a áreas de enfermedad endémica
Vacunas contraindicadas
Vacuna intranasal contra la influenza (vacuna trivalente con virus vivos atenuados) (las personas que conviven con el receptor en el mismo hogar y los cuidadores no deben recibir esta vacuna dentro de las 2 semanas anteriores al contacto con el receptor de un TCMH); vacuna contra el herpes zóster; vacuna contra el bacilo de Calmette y Guérin (BCG); vacuna antipoliomielítica oral (OPV); vacuna contra el cólera; vacuna contra la fiebre tifoidea (oral o intramuscular); vacuna contra el rotavirus.

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47. O'Brien TA, Eastlund T, Peters C, et al.: Autoimmune haemolytic anaemia complicating haematopoietic cell transplantation in paediatric patients: high incidence and significant mortality in unrelated donor transplants for non-malignant diseases. Br J Haematol 127 (1): 67-75, 2004. [PUBMED Abstract]
48. Gerritsen EJ, Stam ED, Hermans J, et al.: Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children. Bone Marrow Transplant 18 (2): 377-82, 1996. [PUBMED Abstract]
49. Shapiro RS, McClain K, Frizzera G, et al.: Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 71 (5): 1234-43, 1988. [PUBMED Abstract]
50. Brunstein CG, Weisdorf DJ, DeFor T, et al.: Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood 108 (8): 2874-80, 2006. [PUBMED Abstract]
51. Blaes AH, Cao Q, Wagner JE, et al.: Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation. Biol Blood Marrow Transplant 16 (2): 287-91, 2010. [PUBMED Abstract]
52. Kuehnle I, Huls MH, Liu Z, et al.: CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95 (4): 1502-5, 2000. [PUBMED Abstract]
53. Styczynski J, Gil L, Tridello G, et al.: Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 57 (6): 794-802, 2013. [PUBMED Abstract]
54. Liu Z, Savoldo B, Huls H, et al.: Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the prevention and treatment of EBV-associated post-transplant lymphomas. Recent Results Cancer Res 159: 123-33, 2002. [PUBMED Abstract]
55. Bollard CM, Heslop HE: T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127 (26): 3331-40, 2016. [PUBMED Abstract]
56. Ferrara JL, Levine JE, Reddy P, et al.: Graft-versus-host disease. Lancet 373 (9674): 1550-61, 2009. [PUBMED Abstract]
57. Przepiorka D, Weisdorf D, Martin P, et al.: 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15 (6): 825-8, 1995. [PUBMED Abstract]
58. Harris AC, Young R, Devine S, et al.: International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 22 (1): 4-10, 2016. [PUBMED Abstract]
59. Levine JE, Braun TM, Harris AC, et al.: A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol 2 (1): e21-9, 2015. [PUBMED Abstract]
60. Srinagesh HK, Özbek U, Kapoor U, et al.: The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease. Blood Adv 3 (23): 4034-4042, 2019. [PUBMED Abstract]
61. Kanakry CG, O'Donnell PV, Furlong T, et al.: Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 32 (31): 3497-505, 2014. [PUBMED Abstract]
62. Bertaina A, Merli P, Rutella S, et al.: HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 124 (5): 822-6, 2014. [PUBMED Abstract]
63. Jacoby E, Chen A, Loeb DM, et al.: Single-Agent Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis after Human Leukocyte Antigen-Matched Related Bone Marrow Transplantation for Pediatric and Young Adult Patients with Hematologic Malignancies. Biol Blood Marrow Transplant 22 (1): 112-8, 2016. [PUBMED Abstract]
64. Jacobsohn DA: Acute graft-versus-host disease in children. Bone Marrow Transplant 41 (2): 215-21, 2008. [PUBMED Abstract]
65. Deeg HJ: How I treat refractory acute GVHD. Blood 109 (10): 4119-26, 2007. [PUBMED Abstract]
66. Jagasia M, Perales MA, Schroeder MA, et al.: Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood 135 (20): 1739-1749, 2020. [PUBMED Abstract]
67. Laisne L, Neven B, Dalle JH, et al.: Ruxolitinib in children with steroid-refractory acute graft-versus-host disease: A retrospective multicenter study of the pediatric group of SFGM-TC. Pediatr Blood Cancer 67 (9): e28233, 2020. [PUBMED Abstract]

La EICH crónica es un síndrome que compromete uno o varios sistemas orgánicos, con características clínicas que se asemejan a las de una enfermedad autoinmunitaria.[1,2] La EICH crónica se suele observar por primera vez después de 2 a 12 meses de un trasplante de células madre hematopoyéticas (TCMH). Tradicionalmente, los síntomas que se presentaban después de 100 días del TCMH se consideraban EICH crónica y los síntomas que se presentaban antes de los 100 días del TCMH se consideraban EICH aguda. Debido a que algunos abordajes del TCMH pueden producir el inicio tardío de una EICH aguda, y las manifestaciones diagnósticas para la EICH crónica se pueden presentar antes de los 100 días, se describieron los siguientes 3 tipos diferenciados de EICH crónica:

Bibliografía

1. Shlomchik WD, Lee SJ, Couriel D, et al.: Transplantation's greatest challenges: advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (1 Suppl 1): 2-10, 2007. [PUBMED Abstract]
2. Bolaños-Meade J, Vogelsang GB: Chronic graft-versus-host disease. Curr Pharm Des 14 (20): 1974-86, 2008. [PUBMED Abstract]
3. Filipovich AH, Weisdorf D, Pavletic S, et al.: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11 (12): 945-56, 2005. [PUBMED Abstract]
4. Shulman HM, Kleiner D, Lee SJ, et al.: Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 12 (1): 31-47, 2006. [PUBMED Abstract]
5. Zecca M, Prete A, Rondelli R, et al.: Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome. Blood 100 (4): 1192-200, 2002. [PUBMED Abstract]
6. Eapen M, Logan BR, Confer DL, et al.: Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival. Biol Blood Marrow Transplant 13 (12): 1461-8, 2007. [PUBMED Abstract]
7. Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369 (9577): 1947-54, 2007. [PUBMED Abstract]
8. Bertaina A, Zecca M, Buldini B, et al.: Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood 132 (24): 2594-2607, 2018. [PUBMED Abstract]
9. Leung W, Ahn H, Rose SR, et al.: A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86 (4): 215-24, 2007. [PUBMED Abstract]
10. Arora M, Klein JP, Weisdorf DJ, et al.: Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. Blood 117 (24): 6714-20, 2011. [PUBMED Abstract]
11. Jacobsohn DA, Arora M, Klein JP, et al.: Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease. Blood 118 (16): 4472-9, 2011. [PUBMED Abstract]
12. Pavletic SZ, Martin P, Lee SJ, et al.: Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 12 (3): 252-66, 2006. [PUBMED Abstract]
13. Inagaki J, Moritake H, Nishikawa T, et al.: Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 21 (11): 1973-80, 2015. [PUBMED Abstract]
14. Cuvelier GDE, Nemecek ER, Wahlstrom JT, et al.: Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria. Blood 134 (3): 304-316, 2019. [PUBMED Abstract]
15. Koc S, Leisenring W, Flowers ME, et al.: Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 100 (1): 48-51, 2002. [PUBMED Abstract]
16. Couriel D, Carpenter PA, Cutler C, et al.: Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 12 (4): 375-96, 2006. [PUBMED Abstract]
17. Martin PJ, Storer BE, Rowley SD, et al.: Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood 113 (21): 5074-82, 2009. [PUBMED Abstract]
18. Jacobsohn DA, Gilman AL, Rademaker A, et al.: Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study. Blood 114 (20): 4354-60, 2009. [PUBMED Abstract]
19. Jurado M, Vallejo C, Pérez-Simón JA, et al.: Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (6): 701-6, 2007. [PUBMED Abstract]
20. Cutler C, Miklos D, Kim HT, et al.: Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108 (2): 756-62, 2006. [PUBMED Abstract]
21. Miklos D, Cutler CS, Arora M, et al.: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood 130 (21): 2243-2250, 2017. [PUBMED Abstract]
22. González Vicent M, Ramirez M, Sevilla J, et al.: Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. J Pediatr Hematol Oncol 32 (8): 589-93, 2010. [PUBMED Abstract]
23. Carpenter PA, Kitko CL, Elad S, et al.: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 21 (7): 1167-87, 2015. [PUBMED Abstract]

La incidencia más alta de mortalidad después de un TCMH se presenta durante los primeros 2 años, en su mayoría por recaída. En un estudio sobre mortalidad tardía (≥2 años postrasplante) en niños con neoplasias malignas se sometieron a TCMH se observó que alrededor del 20 % de 479 pacientes que estaban vivos a los 2 años murieron posteriormente. La mortalidad tardía en el grupo de trasplante alogénico fue del 15 % (mediana de seguimiento de 10,0 años; intervalo, 2,0–25,6 años), sobre todo por recaída (65 %). Entre los pacientes, el 26 % presentaron muerte tardía después de un TCMH autógeno (mediana de seguimiento, 6,7 años; intervalo, 2,0–22,2 años)[1] y el 88 % de estas muertes se produjo por la recidiva de la neoplasia maligna primaria. La mortalidad no relacionada con las recaídas, la muerte por enfermedad de injerto contra huésped (EICH) crónica y las neoplasias malignas secundarias son menos frecuentes en niños.

En otro estudio se analizaron las causas de la mortalidad tardía después de un segundo trasplante alogénico.[2] De los niños que estaban vivos y sin recaída 1 año después del segundo TCMH, un 55 % estaban vivos a los 10 años. En este grupo, la causa más común de mortalidad entre 1 y 10 años después del trasplante fue la recaída (77 % de las muertes), que en su mayoría, se produjeron en los primeros 3 años después del trasplante. La incidencia acumulada de mortalidad sin recaída en esta cohorte a los 10 años fue del 10 %. La EICH crónica se presentó en el 43 % de los niños de este estudio y fue la causa principal de mortalidad sin recaída.

En un estudio centrado en la mortalidad después de un TCMH autógeno en niños, se observó que las tasas de mortalidad seguían siendo mayores a las de la población general más de 10 años después del procedimiento, pero se acercaron a las tasas de la población general a los 15 años. En el estudio, también se observó una disminución de la mortalidad tardía en las épocas más actuales de tratamiento (antes de 1990, 35,1 %; 1990–1999, 25,6 %; 2000–2010, 21,8 %; P = 0,05).[3]

Bibliografía

1. Schechter T, Pole JD, Darmawikarta D, et al.: Late mortality after hematopoietic SCT for a childhood malignancy. Bone Marrow Transplant 48 (10): 1291-5, 2013. [PUBMED Abstract]
2. Duncan CN, Majhail NS, Brazauskas R, et al.: Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 21 (1): 151-8, 2015. [PUBMED Abstract]
3. Holmqvist AS, Chen Y, Wu J, et al.: Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report. Blood 131 (24): 2720-2729, 2018. [PUBMED Abstract]

En los datos provenientes de estudios de adultos y niños sobrevivientes de TCMH se ha observado un efecto importante de las exposiciones relacionadas con el tratamiento en la supervivencia y la calidad de vida.[1] En un estudio de pacientes que estaban con vida 2 años después de someterse a TCMH, los sobrevivientes presentaron un aumento del riesgo de muerte prematura 9,9 veces mayor al de los controles ajustados por edad y sexo de la población general de los Estados Unidos.[2] En otro estudio multicéntrico se demostró que más de la mitad de los supervivientes adultos que se sometieron a un TCMH durante la infancia tenían un problema de salud crónico de grado 3 o 4. Los sobrevivientes tenían una oportunidad relativa (OR) de 15,1 en comparación con sus hermanos.[3]

Bibliografía

1. Sun CL, Francisco L, Kawashima T, et al.: Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood 116 (17): 3129-39; quiz 3377, 2010. [PUBMED Abstract]
2. Bhatia S, Francisco L, Carter A, et al.: Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood 110 (10): 3784-92, 2007. [PUBMED Abstract]
3. Holmqvist AS, Chen Y, Hageman L, et al.: Severe, life-threatening, and fatal chronic health conditions after allogeneic blood or marrow transplantation in childhood. Cancer 129 (4): 624-633, 2023. [PUBMED Abstract]
4. Bhatia S, Robison LL, Francisco L, et al.: Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study. Blood 105 (11): 4215-22, 2005. [PUBMED Abstract]
5. Gooley TA, Chien JW, Pergam SA, et al.: Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363 (22): 2091-101, 2010. [PUBMED Abstract]
6. Martin PJ, Counts GW, Appelbaum FR, et al.: Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol 28 (6): 1011-6, 2010. [PUBMED Abstract]
7. Geenen MM, Cardous-Ubbink MC, Kremer LC, et al.: Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA 297 (24): 2705-15, 2007. [PUBMED Abstract]
8. Oeffinger KC, Mertens AC, Sklar CA, et al.: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355 (15): 1572-82, 2006. [PUBMED Abstract]
9. Bhatia S, Davies SM, Scott Baker K, et al.: NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: etiology and pathogenesis of late effects after HCT performed in childhood--methodologic challenges. Biol Blood Marrow Transplant 17 (10): 1428-35, 2011. [PUBMED Abstract]
10. Behar E, Chao NJ, Hiraki DD, et al.: Polymorphism of adhesion molecule CD31 and its role in acute graft-versus-host disease. N Engl J Med 334 (5): 286-91, 1996. [PUBMED Abstract]
11. Goodman RS, Ewing J, Evans PC, et al.: Donor CD31 genotype and its association with acute graft-versus-host disease in HLA identical sibling stem cell transplantation. Bone Marrow Transplant 36 (2): 151-6, 2005. [PUBMED Abstract]
12. van Dalen EC, van der Pal HJ, Kok WE, et al.: Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42 (18): 3191-8, 2006. [PUBMED Abstract]
13. Duncan CN, Brazauskas R, Huang J, et al.: Late cardiovascular morbidity and mortality following pediatric allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 53 (10): 1278-1287, 2018. [PUBMED Abstract]
14. Chow EJ, Mueller BA, Baker KS, et al.: Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation. Ann Intern Med 155 (1): 21-32, 2011. [PUBMED Abstract]
15. Armenian SH, Sun CL, Francisco L, et al.: Late congestive heart failure after hematopoietic cell transplantation. J Clin Oncol 26 (34): 5537-43, 2008. [PUBMED Abstract]
16. Armenian SH, Sun CL, Mills G, et al.: Predictors of late cardiovascular complications in survivors of hematopoietic cell transplantation. Biol Blood Marrow Transplant 16 (8): 1138-44, 2010. [PUBMED Abstract]
17. Armenian SH, Sun CL, Kawashima T, et al.: Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS). Blood 118 (5): 1413-20, 2011. [PUBMED Abstract]
18. Arvidson J, Kihlgren M, Hall C, et al.: Neuropsychological functioning after treatment for hematological malignancies in childhood, including autologous bone marrow transplantation. Pediatr Hematol Oncol 16 (1): 9-21, 1999 Jan-Feb. [PUBMED Abstract]
19. Barrera M, Atenafu E: Cognitive, educational, psychosocial adjustment and quality of life of children who survive hematopoietic SCT and their siblings. Bone Marrow Transplant 42 (1): 15-21, 2008. [PUBMED Abstract]
20. Kupst MJ, Penati B, Debban B, et al.: Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study. Bone Marrow Transplant 30 (9): 609-17, 2002. [PUBMED Abstract]
21. Phipps S, Brenner M, Heslop H, et al.: Psychological effects of bone marrow transplantation on children and adolescents: preliminary report of a longitudinal study. Bone Marrow Transplant 15 (6): 829-35, 1995. [PUBMED Abstract]
22. Phipps S, Rai SN, Leung WH, et al.: Cognitive and academic consequences of stem-cell transplantation in children. J Clin Oncol 26 (12): 2027-33, 2008. [PUBMED Abstract]
23. Phipps S, Dunavant M, Srivastava DK, et al.: Cognitive and academic functioning in survivors of pediatric bone marrow transplantation. J Clin Oncol 18 (5): 1004-11, 2000. [PUBMED Abstract]
24. Cognitive functioning after BMT. In: Pot-Mees CC: The Psychological Effects of Bone Marrow Transplantation in Children. Eburon Delft, 1989, pp 96–103.
25. Simms S, Kazak AE, Golomb V, et al.: Cognitive, behavioral, and social outcome in survivors of childhood stem cell transplantation. J Pediatr Hematol Oncol 24 (2): 115-9, 2002. [PUBMED Abstract]
26. Cool VA: Long-term neuropsychological risks in pediatric bone marrow transplant: what do we know? Bone Marrow Transplant 18 (Suppl 3): S45-9, 1996. [PUBMED Abstract]
27. Kramer JH, Crittenden MR, DeSantes K, et al.: Cognitive and adaptive behavior 1 and 3 years following bone marrow transplantation. Bone Marrow Transplant 19 (6): 607-13, 1997. [PUBMED Abstract]
28. Kramer JH, Crittenden MR, Halberg FE, et al.: A prospective study of cognitive functioning following low-dose cranial radiation for bone marrow transplantation. Pediatrics 90 (3): 447-50, 1992. [PUBMED Abstract]
29. Shah AJ, Epport K, Azen C, et al.: Progressive declines in neurocognitive function among survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies. J Pediatr Hematol Oncol 30 (6): 411-8, 2008. [PUBMED Abstract]
30. Smedler AC, Bolme P: Neuropsychological deficits in very young bone marrow transplant recipients. Acta Paediatr 84 (4): 429-33, 1995. [PUBMED Abstract]
31. Smedler AC, Winiarski J: Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning. Bone Marrow Transplant 42 (8): 515-22, 2008. [PUBMED Abstract]
32. Willard VW, Leung W, Huang Q, et al.: Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation. J Clin Oncol 32 (35): 3982-8, 2014. [PUBMED Abstract]
33. McDonald GB: Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology 51 (4): 1450-60, 2010. [PUBMED Abstract]
34. Nieder ML, McDonald GB, Kida A, et al.: National Cancer Institute-National Heart, Lung and Blood Institute/pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: long-term organ damage and dysfunction. Biol Blood Marrow Transplant 17 (11): 1573-84, 2011. [PUBMED Abstract]
35. Mackey JR, Desai S, Larratt L, et al.: Myasthenia gravis in association with allogeneic bone marrow transplantation: clinical observations, therapeutic implications and review of literature. Bone Marrow Transplant 19 (9): 939-42, 1997. [PUBMED Abstract]
36. Shimada K, Yokozawa T, Atsuta Y, et al.: Solid tumors after hematopoietic stem cell transplantation in Japan: incidence, risk factors and prognosis. Bone Marrow Transplant 36 (2): 115-21, 2005. [PUBMED Abstract]
37. McDonald GB, Sullivan KM, Schuffler MD, et al.: Esophageal abnormalities in chronic graft-versus-host disease in humans. Gastroenterology 80 (5 pt 1): 914-21, 1981. [PUBMED Abstract]
38. McDonald GB, Sullivan KM, Plumley TF: Radiographic features of esophageal involvement in chronic graft-vs.-host disease. AJR Am J Roentgenol 142 (3): 501-6, 1984. [PUBMED Abstract]
39. Schima W, Pokieser P, Forstinger C, et al.: Videofluoroscopy of the pharynx and esophagus in chronic graft-versus-host disease. Abdom Imaging 19 (3): 191-4, 1994 May-Jun. [PUBMED Abstract]
40. Minocha A, Mandanas RA, Kida M, et al.: Bullous esophagitis due to chronic graft-versus-host disease. Am J Gastroenterol 92 (3): 529-30, 1997. [PUBMED Abstract]
41. Patey-Mariaud de Serre N, Reijasse D, Verkarre V, et al.: Chronic intestinal graft-versus-host disease: clinical, histological and immunohistochemical analysis of 17 children. Bone Marrow Transplant 29 (3): 223-30, 2002. [PUBMED Abstract]
42. Akpek G, Chinratanalab W, Lee LA, et al.: Gastrointestinal involvement in chronic graft-versus-host disease: a clinicopathologic study. Biol Blood Marrow Transplant 9 (1): 46-51, 2003. [PUBMED Abstract]
43. Filipovich AH, Weisdorf D, Pavletic S, et al.: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11 (12): 945-56, 2005. [PUBMED Abstract]
44. McDonald GB, Bouvier M, Hockenbery DM, et al.: Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology 115 (1): 28-35, 1998. [PUBMED Abstract]
45. Hockenbery DM, Cruickshank S, Rodell TC, et al.: A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease. Blood 109 (10): 4557-63, 2007. [PUBMED Abstract]
46. Iyer RV, Hahn T, Roy HN, et al.: Long-term use of oral beclomethasone dipropionate for the treatment of gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 11 (8): 587-92, 2005. [PUBMED Abstract]
47. Borgaonkar MR, Duggan PR, Adams G: Differing clinical manifestations of celiac disease transmitted by bone marrow transplantation. Dig Dis Sci 51 (1): 210-2, 2006. [PUBMED Abstract]
48. Sullivan KM, Shulman HM, Storb R, et al.: Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 57 (2): 267-76, 1981. [PUBMED Abstract]
49. Tomás JF, Pinilla I, García-Buey ML, et al.: Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplant 26 (6): 649-55, 2000. [PUBMED Abstract]
50. Strasser SI, Shulman HM, Flowers ME, et al.: Chronic graft-versus-host disease of the liver: presentation as an acute hepatitis. Hepatology 32 (6): 1265-71, 2000. [PUBMED Abstract]
51. Malik AH, Collins RH, Saboorian MH, et al.: Chronic graft-versus-host disease after hematopoietic cell transplantation presenting as an acute hepatitis. Am J Gastroenterol 96 (2): 588-90, 2001. [PUBMED Abstract]
52. Akpek G, Boitnott JK, Lee LA, et al.: Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion. Blood 100 (12): 3903-7, 2002. [PUBMED Abstract]
53. Shulman HM, Sharma P, Amos D, et al.: A coded histologic study of hepatic graft-versus-host disease after human bone marrow transplantation. Hepatology 8 (3): 463-70, 1988 May-Jun. [PUBMED Abstract]
54. Strasser SI, Myerson D, Spurgeon CL, et al.: Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology 29 (6): 1893-9, 1999. [PUBMED Abstract]
55. Ljungman P, Johansson N, Aschan J, et al.: Long-term effects of hepatitis C virus infection in allogeneic bone marrow transplant recipients. Blood 86 (4): 1614-8, 1995. [PUBMED Abstract]
56. Strasser SI, Sullivan KM, Myerson D, et al.: Cirrhosis of the liver in long-term marrow transplant survivors. Blood 93 (10): 3259-66, 1999. [PUBMED Abstract]
57. Peffault de Latour R, Lévy V, Asselah T, et al.: Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 103 (5): 1618-24, 2004. [PUBMED Abstract]
58. Ko CW, Murakami C, Sekijima JH, et al.: Chemical composition of gallbladder sludge in patients after marrow transplantation. Am J Gastroenterol 91 (6): 1207-10, 1996. [PUBMED Abstract]
59. Akpek G, Valladares JL, Lee L, et al.: Pancreatic insufficiency in patients with chronic graft-versus-host disease. Bone Marrow Transplant 27 (2): 163-6, 2001. [PUBMED Abstract]
60. Maringhini A, Gertz MA, DiMagno EP: Exocrine pancreatic insufficiency after allogeneic bone marrow transplantation. Int J Pancreatol 17 (3): 243-7, 1995. [PUBMED Abstract]
61. Radu B, Allez M, Gornet JM, et al.: Chronic diarrhoea after allogenic bone marrow transplantation. Gut 54 (1): 161, 174, 2005. [PUBMED Abstract]
62. Mariotti E, Angelucci E, Agostini A, et al.: Evaluation of cardiac status in iron-loaded thalassaemia patients following bone marrow transplantation: improvement in cardiac function during reduction in body iron burden. Br J Haematol 103 (4): 916-21, 1998. [PUBMED Abstract]
63. Angelucci E, Muretto P, Lucarelli G, et al.: Treatment of iron overload in the "ex-thalassemic". Report from the phlebotomy program. Ann N Y Acad Sci 850: 288-93, 1998. [PUBMED Abstract]
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143. Chien JW, Zhao LP, Hansen JA, et al.: Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation. Blood 107 (5): 2200-7, 2006. [PUBMED Abstract]
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148. Ellis MJ, Parikh CR, Inrig JK, et al.: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8 (11): 2378-90, 2008. [PUBMED Abstract]
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Los resúmenes del PDQ con información sobre el cáncer se revisan con regularidad y se actualizan a medida que se obtiene nueva información. Esta sección describe los cambios más recientes introducidos en este resumen a partir de la fecha arriba indicada.

Complicaciones graves relacionadas con el trasplante de células madre hematopoyéticas

Se añadió texto para indicar que se cerró un estudio debido a la falta de eficacia, lo que pone en duda la validez del uso profiláctico de la defibrotida (se citó a Grupp et al. como referencia 27).

Se añadió texto para indicar que, aunque no hay ensayos aleatorizados ni prospectivos en los que se haya usado el eculizumab para tratar la microangiopatía trombótica relacionada con el trasplante (TA-TMA), existen datos publicados de estudios retrospectivos institucionales y multicéntricos. En el pasado, la tasa de supervivencia a 1 año para los pacientes con TA-TMA que no recibieron tratamiento fue de alrededor del 20 %. En un estudio de un solo centro se observó una tasa de supervivencia general (SG) a 1 año del 66 % con el tratamiento con eculizumab (se citó a Jodele et al. como referencia 39). También se añadió texto para indicar que en un estudio multicéntrico se notificó una tasa de SG a 6 meses del 47 % con el tratamiento con eculizumab (se citó a Svec et al. como referencia 40).

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